Delineating the placental mechanisms underpinning poor pregnancy outcomes in advanced maternal age and exploring the therapeutic potential of melatoni

在英国，20%的分娩发生在35岁以上的女性(定义为高龄产妇年龄，AMA)，而4%的孕妇超过40岁。与20-30岁的女性相比，患有AMA的女性更有可能生下生长受限的婴儿(胎儿生长受限，FGR)并生下死胎。胎儿生长迟缓和死产都会对家庭产生深远的影响，并对产妇服务造成重大负担。胎盘功能异常是AMA胎盘发育迟缓/死产风险增加的一个重要原因。胎盘对健康的怀孕至关重要，它的关键作用之一是将营养转移到发育中的婴儿。当胎盘功能不正常时，称为胎盘功能障碍，营养物质的转移不足以促进婴儿的正常发育，结果就是FGR。我们已经证明，40岁以上的女性胎盘结构和胎盘功能的某些方面会发生改变。在我们研究小组开发的AMA小鼠模型中也进行了类似的观察。我们不完全了解AMA胎盘改变背后的原因。然而，这一理解对于减少FGR婴儿和大龄母亲死产的数量至关重要。在我们的AMA小鼠模型中，初步实验表明，老年小鼠存在氧化应激和线粒体功能障碍，用褪黑素(一种自然产生的抗氧化荷尔蒙)治疗它们可以减少死产的发生率。该项目将进一步了解为什么高龄孕妇的妊娠结局更差，包括在这个小鼠模型中关注胎盘。我们还计划评估褪黑素在该模型中减少死产的机制，并评估AMA小鼠胎盘功能障碍的时间；这将有助于指导我们在怀孕期间何时应该选择治疗的时机，以防止FGR/死产。该项目将提供对高龄孕妇FGR和死产风险增加的理解，以及褪黑素改善AMA小鼠模型结局的机制。在完成这一博士学位后，候选人将接受全面的动物生理学培训，以及功能生理学研究。因此，这种结合将使学生在获奖后具备理想的技能。

In the UK, 20% of all births occur to women over the age of 35 (defined as advanced maternal age, AMA) whilst 4% of pregnant women are over the age of 40. Women of AMA are more likely to have a baby that is growth restricted (fetal growth restriction, FGR) and to have a stillbirth than women aged 20-30. Both FGR and stillbirth have profound consequences for families and place a significant burden on maternity services. An important reason for the increased risk of FGR/stillbirth in AMA is abnormalities in placental function. The placenta is crucial for a healthy pregnancy and one of its key roles is to transfer nutrients to the developing baby. When the placenta fails to function appropriately, termed placental dysfunction, nutrient transfer is inadequate for normal growth of the baby and FGR is the result. We have demonstrated that placental structure and some aspects of placental function are altered in women over 40 years of age. Similar observations have been made in a mouse model of AMA developed by our research group. We do not fully understand the reasons behind these placental changes in AMA. However, this understanding is vital to reducing the number of FGR babies and stillbirths in older mothers. In our mouse model of AMA, preliminary experiments show evidence of oxidative stress and mitochondrial dysfunction in older mice and that treating them with melatonin, a naturally occurring antioxidant hormone, reduces the incidence of stillbirth. This project will further the knowledge of why pregnancy outcomes are worse in advanced maternal age, including a focus on the placenta in this mouse model. We also plan to assess the mechanisms by which melatonin reduces stillbirth in this model and also to assess the timing of placental dysfunction in AMA mice; this will help to guide us as to when therapies should be timed during pregnancy in order to prevent FGR/stillbirth. This project will provide understanding of the increased risk of FGR and stillbirth in advanced maternal age and the mechanisms by which melatonin improves outcomes in our mouse model of AMA. Following completion of this PhD, the candidate will have received thorough training in whole animal physiology, together with functional physiological studies. This combination will thus equip the student with a desirable skill set post-award.